A zwitterion is a chemical compound that is electrically neutral through a net cancellation of formal positive and negative charges within the compound. Zwitterions are polar and usually have a higher solubility at acid and basic pH values where a net charge exists in the compound. However, at physiologic pH a net zero charge often reduces solubility. This phenomenon is utilized in isoelastic focusing techniques with pH graded media.
Some zwitterions are useful medical therapeutics. Unfortunately, the low solubility of zwitterionic compounds at physiological pH has resulted in low dose high volume administration that limits the pharmokinetics of the agent. Alternatively, the zwitterion is functionalized to increase solubility, but usually at the expense of physiological activity.
In attempting to develop effective modes of administration that are likely to enhance patient compliance, spinal injection has been recognized as an attractive site where a localized therapy in the neuronal area of a patient is necessary. The use of directed intrathecal administration of zwitterionic compound either by bolus injection or by infusion regulated by refillable, implantable pump systems has drastically improved clinical feasibility of administration. Here as well, poor solubility of the zwitterionic therapeutic agent in saline solution necessitates multiple intrathecal pumping cycles to achieve an efficacious dose. Furthermore, when additional modulators are to be combined with the zwitterionic therapeutic agent, the levels of the zwitterionic therapeutic agent dissolvable in the saline solution are reduced.
By way of example, a zwitterionic compound usage as a therapeutic, baclofen, is indicated as a muscle relaxant and antispastic, in aqueous solutions has been extensively investigated. A theoretical upper limit of baclofen solubility is estimated to be 4.3 mg/ml. This is achieved through weeks' or months' dissolution of powder baclofen. The resulting suspension, however, is not suitable for intrathecal delivery. Increased solubility has been achieved in aqueous saline solution to as high as 12 mg/ml through extreme heating at 100° Celsius, intense agitation such as sonication, and high speed stirring. U.S. Patent Application Publication 2006/0009523. The drawbacks of this method are that it is time consuming and requires instrumentation not commonly found in a clinical setting. Another method that has shown some success is by initial dissolution in acid solution with pH levels below 3.87. Just prior to administration a base is added to bring the pH to pharmaceutically acceptable levels. This back titration method produces baclofen concentrations of nearly 10 mg/ml. U.S. Patent Application Publication 2006/0009523. The back titration method, however, required the use of strong acids or bases for the initial baclofen salvation that persist as a component of the clinically delivered baclofen solution. Further, saline solutions suffer neurotoxic complications resulting from their differing pH, osmotic pressure, membrane-active ion concentration, and CO2. Oka, K, et al., Neurosurgery, 1996; 38:733-736; Griffith H B: Endoneurosurgery: Endoscopic intracranial surgery, in Symon L (ed): Advances and Technical Standards in Neurosurgery. Wien, Springer-Verlag, 1986; 4:2-24; Griffith, H B, and Jamjoom A B, Br J Neurosurg, 1990; 4:95-100.
An alternative to saline or other aqueous solution for baclofen administration is artificial cerebrospinal fluid (aCSF). Differing forms of aCSF were previously used for in vivo pharmacological studies of baclofen administration. Jackson, G L, et al., Endocrinology, 2000; 141: 3940-3945; Goda, R. et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2004; 801:257-64. However, the baclofen concentrations achieved in these and other studies were less than 0.21 mg/ml.
Similar to baclofen, a variety of therapeutics have indications for cerebrospinal administration are also zwitterions at physiological pH. These therapeutic zwitterions have a variety of activities inclusive of neurotransmitter agonists and antagonists, antibiotics, anti-inflammatories, psychotropics, and neurotransmitter mimics. As with baclofen, the poor solubility of these therapeutic zwitterions has limited therapeutic efficacy owing to the large carrier volumes needed to solubilize needed doses.
Thus, there exists a need for a formulation whereby the solubility of a zwitterionic therapeutic agent is increased relative to conventional techniques. There further exists a need for a high concentration zwitterionic therapeutic agent that is amenable to storage and delivery by common routes such as intravenous, intramuscular and intrathecal.